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Gheorghiade M.,Northwestern University | Larson C.J.,Cardiovascular and Metabolic Diseases Drug Discovery Unit | Shah S.J.,Northwestern University | Greene S.J.,Duke University | And 19 more authors.
Circulation: Heart Failure | Year: 2016

Compared with heart failure (HF) care 20 to 30 years ago, there has been tremendous advancement in therapy for ambulatory HF with reduced ejection fraction with the use of agents that block maladaptive neurohormonal pathways. However, during the past decade, with few notable exceptions, the frequency of successful drug development programs has fallen as most novel therapies have failed to offer incremental benefit or raised safety concerns (ie, hypotension). Moreover, no therapy has been approved specifically for HF with preserved ejection fraction or for worsening chronic HF (including acutely decompensated HF). Across the spectrum of HF, preliminary results from many phase II trials have been promising but are frequently followed by unsuccessful phase III studies, highlighting a disconnect in the translational process between basic science discovery, early drug development, and definitive clinical testing in pivotal trials. A major unmet need in HF drug development is the ability to identify homogeneous subsets of patients whose underlying disease is driven by a specific mechanism that can be targeted using a new therapeutic agent. Drug development strategies should increasingly consider therapies that facilitate reverse remodeling by directly targeting the heart itself rather than strictly focusing on agents that unload the heart or target systemic neurohormones. Advancements in cardiac imaging may allow for more focused and direct assessment of drug effects on the heart early in the drug development process. To better understand and address the array of challenges facing current HF drug development, so that future efforts may have a better chance for success, the Food and Drug Administration facilitated a meeting on February 17, 2015, which was attended by clinicians, researchers, regulators, and industry representatives. The following discussion summarizes the key takeaway dialogue from this meeting. © 2016 American Heart Association, Inc.


Kirchhof P.,University of Munster | Lip G.Y.H.,University of Birmingham | Van Gelder I.C.,University of Groningen | Bax J.,Leiden University | And 52 more authors.
Europace | Year: 2012

While management of atrial fibrillation (AF) patients is improved by guideline-conform application of anticoagulant therapy, rate control, rhythm control, and therapy of accompanying heart disease, the morbidity and mortality associated with AF remain unacceptably high. This paper describes the proceedings of the 3rd Atrial Fibrillation NETwork (AFNET)/European Heart Rhythm Association (EHRA) consensus conference that convened over 60 scientists and representatives from industry to jointly discuss emerging therapeutic and diagnostic improvements to achieve better management of AF patients. The paper covers four chapters: (i) risk factors and risk markers for AF; (ii) pathophysiological classification of AF; (iii) relevance of monitored AF duration for AF-related outcomes; and (iv) perspectives and needs for implementing better antithrombotic therapy. Relevant published literature for each section is covered, and suggestions for the improvement of management in each area are put forward. Combined, the propositions formulate a perspective to implement comprehensive management in AF. © The Author 2011. For permissions please.


Bui A.H.,Harvard University | Cannon C.P.,Harvard University | Steg P.G.,French Institute of Health and Medical Research | Steg P.G.,Departement Hospitalo University | And 13 more authors.
Circulation: Arrhythmia and Electrophysiology | Year: 2016

Background-Nonsustained ventricular tachycardia (NSVT) is common after acute coronary syndrome (ACS) and a marker of increased risk of arrhythmogenic death. However, the prognostic significance of NSVT when evaluated with other contemporary risk markers and at later time points after ACS remains uncertain. Methods and Results-In the Platelet Inhibition and Patient Outcomes (PLATO) trial, continuous ECGs were performed during the first 7 days after ACS (n=2866) and repeated for another 7 days at day 30 (n=1991). Median follow-up was 1 year. There was a time-varying interaction between NSVT and cardiovascular death such that NSVT was significantly associated with increased risk within the first 30 days after randomization (22/999 [2.2%] versus 16/1825 [0.9%]; adjusted hazard ratio, 2.84; 95% confidence interval, 1.39-5.79; P=0.004) but not after 30 days (28/929 [3.0%] versus 42/1734 [2.4%]; P=0.71). Detection of NSVT during the convalescent phase (n=428/1991; 21.5%) was also associated with an increased risk of cardiovascular death, and was most marked within the first 2 months after detection (1.9% versus 0.3%; adjusted hazard ratio, 5.48; 95% confidence interval, 1.07-28.20; P=0.01), and then decreasing over time such that the relationship was no longer significant by ≈5 months after ACS. Conclusions-NSVT occurred frequently during the acute and convalescent phases of ACS. The risk of cardiovascular death associated with NSVT was the greatest during the first 30 days after presentation; however, patients with NSVT detected during the convalescent phase were also at a significantly increased risk of cardiovascular death that persisted for an additional several months after the index event. © 2016 American Heart Association, Inc.


Johnson D.M.,Maastricht University | De Jong M.M.J.,Maastricht University | Crijns H.J.G.M.,Maastricht University | Carlsson L.G.,Astra Zeneca Research and Development | Volders P.G.A.,Maastricht University
Circulation: Arrhythmia and Electrophysiology | Year: 2012

Background-AZD1305 is an investigational antiarrhythmic agent for management of atrial fibrillation. It blocks various cardiac ion currents at different potencies and has atrial-predominant electrophysiological effects. We investigated the electrophysiological and proarrhythmic effects of AZD1305 versus dofetilide in dogs with chronic complete atrioventricular block and myocardial hypertrophic remodeling. Methods and Results-AZD1305 was administered to anesthetized mongrel dogs before and >2 weeks after the induction of atrioventricular block and ventricular and atrial electrophysiological parameters were assessed. In all dogs, the selective IKr blocker dofetilide was used to examine susceptibility to acquired torsades de pointes in chronic atrioventricular block and for comparison. At normal sinus rhythm, AZD1305 increased QT and RR intervals from 290 ± 7 to 397 ± 15 ms (≈37%, P <0.0001) and from 603 ± 22 to 778 ± 32 ms (≈29%, p <0.002), respectively. In the same animals at chronic atrioventricular block, AZD1305 increased the QT interval from 535 ± 28 to 747 ± 36 ms (≈40%, P <0.0001), similar to the QT prolongation by dofetilide (511 ±22 to 703 ± 45 ms [≈38%, P <0.0001]). AZD1305 slightly slowed the idioventricular rhythm. Whereas all (n=14) chronic atrioventricular block animals exhibited torsades de pointes on dofetilide, the arrhythmia was induced in only 4 of 11 dogs after AZD1305. Beat-to-beat variability of left-ventricular monophasic-action-potential duration increased after dofetilide (2.3 ±0.2 to 6.3 ± 0.7 ms; P <0.0001) but not after AZD1305 (2.8 ± 0.3 to 3.7 ± 0.3 ms; p <0.20) despite similar left-ventricular monophasic-action-potential duration prolongations. Conclusions-Despite causing similar degrees of repolarization delay as the selective IKr blocker dofetilide, the combined ion-channel blocker AZD1305 induces less repolarization instability and has a lower ventricular proarrhythmic potential in the remodeled dog heart. © 2011 American Heart Association, Inc.

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